The present invention relates to substituted 5-amino-imidazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine adenosine A2a receptor antagonists, the use of said compounds in the treatment of central nervous system diseases, in particular Parkinson""s disease, and to pharmaceutical compositions comprising said compounds.
Adenosine is known to be an endogenous modulator of a number of physiological functions. At the cardiovascular system level, adenosine is a strong vasodilator and a cardiac depressor. On the central nervous system, adenosine induces sedative, anxiolytic and antiepileptic effects. On the respiratory system, adenosine induces bronchoconstriction. At the kidney level, it exerts a biphasic action, inducing vasoconstriction at low concentrations and vasodilation at high doses. Adenosine acts as a lipolysis inhibitor on fat cells and as an antiaggregant on platelets.
Adenosine action is mediated by the interaction with different membrane specific receptors which belong to the family of receptors coupled with G proteins. Biochemical and pharmacological studies, together with advances in molecular biology, have allowed the identification of at least four subtypes of adenosine receptors: A1, A2a, A2b and A3. A1 and A3 are high-affinity, inhibiting the activity of the enzyme adenylate cyclase, and A2a and A2b are low-affinity, stimulating the activity of the same enzyme. Analogs of adenosine able to interact as antagonists with the A1, A2, A2b and A3 receptors have also been identified.
Selective antagonists for the A2a receptor are of pharmacological interest because of their reduced level of side affects. In the central nervous system, A2a antagonists can have antidepressant properties and stimulate cognitive functions. Moreover, data has shown that A2a receptors are present in high density in the basal ganglia, known to be important in the control of movement. Hence, A2a antagonists can improve motor impairment due to neurodegenerative diseases such as Parkinson""s disease, senile dementia as in Alzheimer""s disease, and psychoses of organic origin.
Some xanthine-related compounds have been found to be A1 receptor selective antagonists, and xanthine and non-xanthine compounds have been found to have high A2a affinity with varying degrees of A2a vs. A1 selectivity. Triazolo-pyrimidine adenosine A2a receptor antagonists with different substitution at the 7-position have been disclosed previously, for example in WO 95/01356; U.S. Pat. No. 5,565,460; WO 97/05138; WO 98/52568 and US Provisional Application 60/334,342. Pyrazolo-substituted triazolo-pyrimidine adenosine A2a receptor antagonists are disclosed in WO 01/92264.
The present invention relates to a compound represented by the structural formula I 
or a pharmaceutically acceptable salt thereof, wherein
R is R1-heteroaryl, R10-phenyl, C4-C6 cycloalkenyl, xe2x80x94C(xe2x95x90CH2)CH3, xe2x80x94Cxe2x89xa1Cxe2x80x94CH3, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94OR2, xe2x80x94CHxe2x95x90C(CH3)2, 
X is C1-C6 alkylene, xe2x80x94C(O)CH2xe2x80x94 or xe2x80x94C(O)N(R2)CH2xe2x80x94;
Y is xe2x80x94N(R2)CH2CH2N(R3)xe2x80x94, xe2x80x94OCH2CH2N(R2)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2Sxe2x80x94, xe2x80x94(CH2)2-3N(R2)xe2x80x94, R5-divalent heteroaryl, 
and Z is R5-phenyl, R5-phenyl(C1-C6)alkyl, R5-heteroaryl, R5-bicyclic heteroaryl, R5-benzofused heteroaryl, diphenylmethyl or R6xe2x80x94C(O)xe2x80x94;
or when Y is 
Z is also R1xe2x80x94SO2xe2x80x94, R7xe2x80x94N(R8)xe2x80x94C(O)xe2x80x94, R7xe2x80x94N(R8)xe2x80x94C(S)xe2x80x94 or R6OC(O)xe2x80x94;
or when Q is 
Z is also phenylamino or pyridylamino;
or Z and Y together are 
or Y and Z together form a piperidinyl or pyrrolidinyl ring fused to a monocyclic or bicyclic aryl or a monocyclic or bicyclic heteroaryl ring wherein X is attached to the N atom of the piperidinyl or pyrrolidinyl ring;
R1 is 1 to 3 substituents independently selected from hydrogen, C1-C6-alkyl, xe2x80x94CF3, halogen, xe2x80x94NO2, xe2x80x94NR12R13, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6, alkylsulfonyl, xe2x80x94COOR7 or xe2x80x94C(O)NR2R3;
R2 and R3 are independently selected from the group consisting of hydrogen and C1-C6 alkyl;
m and n are independently 2-3;
p and q are independently 0-2;
Q and Q1 are independently selected from the group consisting of 
provided that at least one of Q and Q1 is 
R4 is 1-2 substituents independently selected from the group consisting of hydrogen, C1-C6alkyl, R1-aryl and R1-heteroaryl, or two R4 substituents on the same carbon can form xe2x95x90O;
R5 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, xe2x80x94CN, dixe2x80x94((C1-C6)alkyl)amino, xe2x80x94CF3, xe2x80x94OCF3, acetyl, xe2x80x94NO2, hydroxy(C1-C6)alkoxy, (C1-C6)-alkoxy(C1-C6)alkoxy, dixe2x80x94((C1-C6)-alkoxy)(C1-C6)alkoxy, (C1-C6)-alkoxy(C1-C6)alkoxyxe2x80x94(C1-C6)-alkoxy, carboxy(C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl(C1-C6)alkoxy, (C3-C6)cycloalkyl(C1-C6)alkoxy, dixe2x80x94((C1-C6)alkyl)amino(C1-C6)alkoxy, morpholinyl, (C1-C6)alkylxe2x80x94SO2xe2x80x94, (C1-C6)alkylxe2x80x94SO2-(C1-C6)alkoxy, tetrahydropyranyloxy, (C1-C6)alkylcarbonyl(C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl, (C1-C6)alkylcarbonyloxy(C1-C6)-alkoxy, xe2x80x94SO2NH2, phenoxy, 
(R2O)2xe2x80x94P(O)xe2x80x94CH2xe2x80x94Oxe2x80x94 and (R2O)2xe2x80x94P(O)xe2x80x94; or adjacent R5 substituents together are xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CF2xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94CF2CF2xe2x80x94Oxe2x80x94 and form a ring with the carbon atoms to which they are attached;
R6 is (C1-C6)alkyl, R5-phenyl, R5-phenyl(C1-C6)alkyl, thienyl, pyridyl, (C3-C6)xe2x80x94cycloalkyl, (C1-C6)alkylxe2x80x94OC(O)xe2x80x94NHxe2x80x94(C1-C6)alkylxe2x80x94, dixe2x80x94((C1-C6)alkyl)aminomethyl, or 
R7 is (C1-C6)alkyl, R5-phenyl or R5-phenyl(C1-C6)alkyl;
R8 is hydrogen or C1-C6 alkyl; or R7 and R8 together are xe2x80x94(CH2)pxe2x80x94Axe2x80x94(CH2)q, wherein p and q are independently 2 or 3 and A is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94or xe2x80x94Oxe2x80x94, and form a ring with the nitrogen to which they are attached;
R9 is 1-2 substituents independently selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, halogen, xe2x80x94CF3 and (C1-C6)alkoxy-(C1-C6)alkoxy;
R10 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, xe2x80x94CN, xe2x80x94NH2, C1-C6alkylamino, dixe2x80x94((C1-C6)alkyl)amino, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94S(O)0-2(C1-C6)alkyl and xe2x80x94CH2xe2x80x94SO2-phenyl;
R11 is H, C1-C6 alkyl, phenyl, benzyl, C2-C6 alkenyl, C1-C6 alkoxy(C1-C6)alkyl, di-((C1-C6)alkyl)amino(C1-C6)alkyl, pyrrolidinyl(C1-C6)alkyl or piperidino(C1-C6)alkyl;
R12 is H or C1-C6 alkyl;
R13 is H, (C1-C6)alkylxe2x80x94C(O)xe2x80x94 or (C1-C6)alkylxe2x80x94SO2xe2x80x94;
R14 is H, halogen, C1-C6 alkyl, hydroxy(C1-C6)alkyl, C1-C6 alkoxy(C1-C6)alkyl, thio(C1-C6)alkyl, (C1-C6)alkylthio(C1-C6)alkyl or NR2R3xe2x80x94(C1-C6)alkyl; and
R15 is H, halogen, C1-C6 alkyl or C1-C6 alkoxy.
Another aspect of the invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I in a pharmaceutically acceptable carrier.
Yet another aspect of the invention is a method of treating central nervous system diseases such as depression, cognitive diseases and neurodegenerative diseases such as Parkinson""s disease, senile dementia or psychoses of organic origin, or stroke, comprising administering a compound of formula I to a mammal in need of such treatment. In particular, the invention is drawn to the method of treating Parkinson""s disease comprising administering a compound of formula I to a mammal in need of such treatment.
Still another aspect of the invention is a method of treating Parkinson""s disease with a combination of a compound of formula I and one or more agents useful in the treatment of Parkinson""s disease, for example dopamine; a dopaminergic agonist; an inhibitor of monoamine oxidase, type B (MAO-B); a DOPA decarboxylase inhibitor (DCI); or a catechol-O-methyltransferase (COMT) inhibitor. Also claimed is a pharmaceutical composition comprising a compound of formula I and one or more agents known to be useful in the treatment of Parkinson""s in a pharmaceutically acceptable carrier.
Referring to compounds of formula I above, preferred compounds of formula I are those wherein R is R1-furanyl, R1-thienyl, R1-pyrrolyl, R1-pyridyl or R10-phenyl, more preferably R1-furanyl or R10-phenyl. R1 is preferably hydrogen or halogen. R10 is preferably hydrogen, halogen, alkyl or xe2x80x94CF3. Another group of preferred compounds is that wherein X is alkylene, preferably ethylene. Y is preferably 
wherein Q is 
with Q preferably being nitrogen. Preferably, m and n are each 2, and R4 is H. A preferred definition for Z is R5-phenyl or R5-heteroaryl. R5 is preferably H, halogen, alkyl, alkoxy, hydroxyalkoxy or alkoxyalkoxy. R6 is preferably R5-phenyl. R14 is preferably hydrogen.
When Y and Z together form a piperidinyl or pyrrolidinyl ring fused to a monocyclic or bicyclic aryl or heteroaryl ring, preferred fused ring structures are 
wherein A1 is 
and A2 and A3 each are xe2x80x94C(R16)(R17)xe2x80x94, or
A1 and A3 each are xe2x80x94C(R16)(R 17)xe2x80x94 and A2 is 
or
A1 and A2 each are xe2x80x94C(R16)(R17)xe2x80x94, and A3 is 
A4 is xe2x80x94C(R16)(R17)xe2x80x94;
J1, J2, J3 and J4 are selected from the group consisting of xe2x80x94Nxe2x95x90 and xe2x80x94C(R18)xe2x80x94, provided that 0-2 of J1, J2, J3 or J4 are xe2x80x94Nxe2x95x90 and the remainder are xe2x80x94C(R18)xe2x80x94;
J5 is xe2x80x94N(R17)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94C(R16)(R17)xe2x80x94;
J6 is xe2x80x94Nxe2x95x90 or xe2x80x94C(R18)xe2x80x94;
J7 is xe2x80x94Nxe2x95x90 or xe2x80x94C(R18)xe2x80x94;
t is 0 or 1;
each R16 is independently selected from the group consisting of hydrogen, C1-C6-alkyl, C1-C6-alkoxy, xe2x80x94CF3, halogen, xe2x80x94OH and NO2;
each R17 is independently selected from the group consisting of hydrogen and C1-C6 alkyl; and
each R18 is independently selected from the group consisting of hydrogen, C1-C6-alkyl, CF3, halogen, NO2, C1-C6-alkoxy, xe2x80x94Oxe2x80x94C(O)xe2x80x94(C1-C6-alkyl), xe2x80x94NH2, xe2x80x94NH(C1-C6-alkyl), xe2x80x94N(C1-C6-alkyl)2, xe2x80x94NHxe2x80x94C(O)xe2x80x94(C1-C6-alkyl), xe2x80x94NHxe2x80x94SO2xe2x80x94(C1-C6-alkyl), xe2x80x94SO2NH(C1-C6-alkyl), xe2x80x94SO2N(C1-C6-alkyl)2, xe2x80x94SO2NH2 and xe2x80x94OH.
In the above structures, when A1, A2 or A3 is 
two of the bonds are part of the ring and the third bond joins the ring to the variable X.
In the definition of Q and Q1, 
means that one of Q and Q1 can be nitrogen and the other is selected from the remaining groups, both are nitrogen, both are CH, or one is CH and the other is selected from the remaining groups.
As used herein, the term alkyl includes straight or branched chains. Alkylene, referring to a divalent alkyl group, similarly refers to straight or branched chains. Cycloalkylene refers to a divalent cycloalkyl group. Cycloalkenyl refers to a C4-C6 cycloalkyl ring comprising one double bond.
Aryl means phenyl or naphthyl.
Heteroaryl means a single ring heteroaromatic group of 5 to 6 atoms comprised of 2 to 5 carbon atoms and 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, provided that the rings do not include adjacent oxygen and/or sulfur atoms. Examples of single-ring heteroaryl groups are pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl and triazolyl. Bicyclic heteroaryl means a bicyclic heteroaromatic group of 5 to 10 atoms comprised of 1 to 9 carbon atoms and 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, provided that the rings do not include adjacent oxygen and/or sulfur atoms. Examples of bicyclic heteroaryl groups are naphthyridyl (e.g., 1, 5 or 1,7), imidazopyridyl, pyrido[2,3]imidazolyl, pyridopyrimidinyl and 7-azaindolyl. Benzofused heteroaryl bicyclic groups comprise a heteroaryl ring as defined above fused at adjacent carbon atoms to a phenyl ring. Examples of benzofused heteroaryl groups are indolyl, quinolyl, isoquinolyl, phthalazinyl, benzothienyl (i.e., thionaphthenyl), benzimidazolyl, benzofuranyl, benzoxazolyl and benzofurazanyl. All positional isomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl. N-oxides of the ring nitrogens for all heteroaryl groups are also included. R5-substituted heteroaryl refers to such groups wherein substitutable ring carbon atoms have a substituent as defined above.
Divalent heteroaryl means a heteroaryl ring bonded to two different groups. In the context of this invention, when Y is divalent R5-heteroaryl, one ring member is attached to the variable X, and another ring member is attached to variable Z; the R5 substituents are attached to the remaining ring members. Divalent heteroaryl groups are named by adding xe2x80x9cdiylxe2x80x9d to the name of the ring, for example, a pyridinediyl ring is shown: 
Certain compounds of the invention may exist in different stereoisomeric forms (e.g., enantiomers, diastereoisomers and atropisomers). The invention contemplates all such stereoisomers both in pure form and in mixture, including racemic mixtures.
Certain compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
Certain basic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.
All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Compounds of formula I are prepared by methods known in the art. Preferably, the compounds of formula I are prepared by the methods shown in the following reaction schemes.
In the reaction schemes and the examples that follow, the following abbreviations are used: Ts (tosyl); Bn (benzyl); Me (methyl); Et (ethyl); and Ac (acetyl).
In Scheme 1, alkylation of a 5-amino-imidazolo[4,3-e]-[1,2,4]-triazolo-[1,5-c]pyrimidine of formula II is used to prepare compounds of formula I: 
Starting materials of formula II can be reacted with an alkyl diol ditosylate and a base such as NaH in an inert solvent such as dimethylformamide (DMF), or with a chloro-bromo- or dibromo-alkyl compound under similar conditions, to obtain the 7- and 9-alkyl-substituted intermediates of formula IIIa and III b. The compound of formula IIIa is then reacted with an amine of the formula Zxe2x80x94Yxe2x80x94H in an inert solvent such as DMF at an elevated temperature to obtain a compound of formula Ia, i.e., a compound of formula I wherein X is alkylene.
Alternatively, starting materials of formula II can be reacted with a compound of formula Zxe2x80x94Yxe2x80x94Xxe2x80x94Cl and a base such as NaH in an inert solvent such as DMF to obtain a mixture of a 7-substituted compound of formula I and the corresponding 9-substituted compound.
Compounds of formula II can be prepared using the general procedure described in Scheme 2. 
Commercially available 2-amino-6-bromo purine or 2-amino-6-choloro purine can be reacted with the corresponding hydrazide in butanol at elevated temperatures to produce the displacement product, which can be treated with N,O-bis (trimethylsilyl) acetamide to produce II.
To prepare compounds of formula I wherein Y is piperazinyl and Z is R6xe2x80x94C(O)xe2x80x94, R6xe2x80x94SO2xe2x80x94, R6xe2x80x94OC(O)xe2x80x94, R7xe2x80x94N(R8)xe2x80x94C(O)xe2x80x94 or R7xe2x80x94N(R8)xe2x80x94C(S)xe2x80x94, a compound of formula I wherein Zxe2x80x94Y is 4-t-butoxycarbonyl-1-piperazinyl is deprotected, for example by reaction with an acid such as HCl. The resultant free piperazinyl compound, IV, is treated according to procedures well known in the art to obtain the desired compounds. The following Scheme 3 summarizes such procedures: 
Another method for preparing compounds of formula I is shown in Scheme 4: 
In this procedure, chloroimidazo-pyrimidine V, wherein R20 is as defined above, is reacted with a compound of formula Zxe2x80x94Yxe2x80x94Xxe2x80x94Cl in a manner similar to the alkylation procedure of Scheme 1, and the resultant intermediate is reacted with a hydrazide of formula H2Nxe2x80x94NHxe2x80x94C(O)xe2x80x94R (or with hydrazine hydrate, followed by a compound of formula Clxe2x80x94C(O)xe2x80x94R). The resultant hydrazide undergoes dehydrative rearrangement, e.g., by treatment with N,O-bis-(trimethylsilyl)acetamide (BSA) or a combination of BSA and hexamethyldisilazane (HMDS) and at elevated temperatures.
Starting materials are known or are prepared by processes known in the art.
Another method for preparing compounds of formula I is illustrated in the following Scheme 5: 
In analogy to Scheme 1, chloride V is converted into alkylated compound XII, and this is further reacted with XIV, where R1is preferably t-butyl or benzyl, to obtain derivative XIII. A solvent such as DMF may be employed at a temperature of 60-120xc2x0 C. This is then reacted as in Scheme 1 to furnish XV. The Rxe2x80x2 group is next removed, such as removal of a t-butyl group with HCl or trifluoroacetic acid (TFA), furnishing hydrazine XVI. Acylation of XVI furnishes XVII, which is subjected to dehydrative cyclization as described above to provide desired Ia. Alternatively, XII may be reacted with a hydrazide XVIII to obtain XIX, which can be converted to XVII analogously to preparation of XV.
To prepare compounds of formula IIa, wherein R14 is other than hydrogen, the following procedure can be used: 
The amide of formula XIX is prepared by reacting the pyrimidine of formula XVIII and the acid chloride or anhydride in the presence of a base such as NaOH, and the compound of formula XIX is then cyclized using a reagent such as POCl3 to obtain the chloroimidazolo-pyrimidine of formula Va. The compound of formula Va is reacted with the hydrazide as described in Scheme 2 to obtain the intermediate IIa, which can then be used to prepare a compound of formula I as described in Scheme 1. Compound XVIII, the acid chlorides and the hydrazines are known or can be prepared by processes known in the art.
Schemes 7 to 10 show procedures for preparing starting materials for compounds wherein Y and Z together form an aryl- or heteroaryl- fused piperidinyl or pyrrolidinyl group. The resultant Yxe2x80x94Z portions can be reacted with a compound of formula IIIa as described in Scheme 1 to obtain the desired compounds of formula I. The aromatic portions of the fused ring groups are substituted by independently selected R18 groups, designated in the schemes as R18xe2x80x2, R18xe2x80x3 and R18xe2x80x3. 
Benzyl piperidinone is cyclized with an aminoacrylaldehyde of formula XX to form the benzyl protected tetrahydronaphthyridine of formula XXI, followed by hydrogenolysis to obtain the compound of formula XXII. 
Quaternization of a naphthyridine of formula XXIII followed by reduction gives a benzyl protected tetrahydronaphthyridine of formula XXIa. Hydrogenolysis provides the desired product of formula XXIIa. 
[2+2+2] cyclization of a diyne of formula XXIV with an acetylene of formula XXV provides the benzyl protected isoindoline of formula XXVI. Hydrogenolysis provides the desired compound of formula XXVII. 
Pictet-Spengler cyclization of a phenethylamine of formula XXVIII gives a substituted tetrahydroisoquinoline of formula XXIX.
Using the above procedures, the following compounds were prepared. 
Step 1: Heat a mixture of 2-amino-6-bromo purine (1.0 g, 4.7 mmol) and 2-furoic hydrazide (0.88 g, 7.0 mmol) in butanol (10 ml) at 120xc2x0 C. overnight. Collect the solid by filtration, wash with CH3OH and dry the solid in vacuum oven to produce a white solid. MS (ESI): M+1=260.1. PMR (DMSO) xcex4 6.71 (d, J=1.6 Hz, 1H), 7.32 (s, 1H), 7.41 (bs, 2H), 7.96 (s, 1H), 8.19 (s, 1H), 10.40 (bs, 1H), 10.86 (s, 1H).
Step 2: Heat the product of Step 1(1.3 g, 5 mmol) in N, O-bis (trimethylsilyl) acetamide (6.10 g, 30 mmol) at 100xc2x0 C. overnight. Cool the reaction mixture and pour it on ice water and stir for 4 h. Collect the solid by filtration and wash with CH3OH, Et2O and dry to produce a white solid.
MS(ESI): M+1=242. PMR(DMSO) xcex4 6.71 (dd, J=1.7 and 3.4 Hz, 1H), 7.21 (d, J=2.9 Hz, 1H), 7.67 (s, 1H), 7.92 (s, 1H), 7.99 (s, 1H).
Step 3: Combine the product of Step 2 (5.0 g, 20.7 mmol) and ethylene glycol ditosylate (8.45 g, 22.8 mmol ) in dry DMF (30 ml). Cool the reaction mixture to 0xc2x0 C. under N2. Add NaH (60% in oil, 0.91 g, 22.8 mmol) in portions, keeping internal temperature at 0xc2x0 C. Warm the reaction mixture to room temperature and stir overnight. Pour the reaction mixture on ice/water and stir for 4 h. Collect the solid by filtration and chromatograph it on silica gel to produce the title compound.
MS (ESI): M+1=440.10, PMR (DMSO) xcex4 1.98 (s, 3H), 4.38 (d, J=4.3 Hz, 2H), 4.47 (t, J=4.4 Hz, 2H), 6.72 (dd, J=1.7 and 3.4 Hz, 1H), 6.96 (d, J=8.1 Hz, 2H), 1H), 7.32 (d, J=8.2 Hz, 2H), 7.73 (s, 2H), 7.93 (s, 1H), 7.94 (d, J=0.8
In a similar manner to Preparation 1, but employing the corresponding hydrazide, the following compounds were prepared: